The present invention relates generally to cytokine receptors and more specifically to a method of using tumor necrosis factor antagonists to suppress TNF-dependent inflammatory diseases.
Tumor necrosis factor-.alpha.(TNF.alpha., also known as cachectin) and tumor necrosis factor-.beta. (TNF.beta., also known as lymphotoxin) are homologous mammalian endogenous secretory proteins capable of inducing a wide variety of effects on a large number of cell types. The great similarities in the structural and functional characteristics of these two cytokines have resulted in their collective description as "TNF." Complementary cDNA clones encoding TNF.alpha. (Pennica et al., Nature 312:724, 1984) and TNF.beta. (Gray et al., Nature 312:721, 1984) have been isolated, permitting further structural and biological characterization of TNF.
TNF proteins initiate their biological effect on cells by binding to specific TNF receptor (TNFR) proteins expressed on the plasma membrane of a TNF-responsive cell. Two distinct forms of TNFR are known to exist: Type I TNFR (TNFRI), having a molecular weight of approximately 75 kilodaltons, and Type II TNFR (TNFRII), having a molecular weight of approximately 55 kilodaltons. TNFRI and TNFRII each bind to both TNF.alpha. and TNF.beta.. TNFRI and TNFRII have both been molecularly cloned (Smith et al., Science 248:1019, 1990; Loetscher et al., Cell 61:351, 1990 and Schall et al., Cell 61:361, 1990), permitting recombinant expression and purification of soluble TNFR proteins.
Soluble TNF binding proteins from human urine have also been identified (Peetre et al., Eur. J. Haematol. 41:414, 1988; Seckinger et al., J. Exp. Med. 167:1511, 1988; Seckinger et al., J. Biol. Chem. 264:11966, 1989; UK Patent Application, Publ. No. 2 218 101 A to Seckinger et al.; Engelmann et al., J. Biol. Chem. 264:11974, 1989).
TNF antagonists, such as soluble TNFR and TNF binding proteins, bind to TNF and prevent TNF from binding to cell membrane bound TNF receptors. Such proteins may therefore be useful to suppress biological activities caused by TNF.
The role of TNF in mediated inflammatory diseases and the in vivo biological effects of such soluble TNFR and TNF binding protein proteins in suppressing such TNF-dependent inflammatory diseases have not been fully elucidated and potential therapeutic uses for TNF antagonists have yet to be identified.